This application for a U01 cooperative agreement award is in response to Program Announcement (PA) number PAR-08-004, International Research Collaboration on Alcohol and Alcoholism. The award will enable an international collaboration between two INSERM sites in France (Orsay and Caen) and our US neuroscience laboratories to investigate the consequences of chronic alcoholism on central nervous system structure and function. Our international collaboration provides a unique opportunity to examine within and across cultural variation a broad range of alcoholism-related neuropathology, measured in vivo with structural magnetic resonance imaging (MRI); brain microstructure, circuitry, and tissue quality, measured with diffusion tensor imaging (DTI); and selective brain functions, measured with functional MRI (fMRI) and neuropsychological tests of component processes of cognition, memory, and motor abilities. Human alcoholism is marked by considerable heterogeneity in its consequences on brain structure and function. This multi-site project will be an efficient approach for testing the overarching hypothesis that the heterogeneity of alcoholic consequences on brain structure and function are due substantially to individual differences in pattern of alcohol use, nutritional status, and history of withdrawal symptoms. In both the US and France, the target subject samples will span clinical manifestations from uncomplicated alcoholics to those with the profound amnesia of Korsakoff's Syndrome (KS) and will enable testing of hypotheses about factors contributing to the heterogeneity of alcoholism neuropathology. The Specific Aims of this proposal are to 1. Determine the influence of three classes of clinical variables-drinking pattern, nutritional history and status, and withdrawal history-on a) Alcoholism-related brain dysmorphology measured on legacy and prospective MRI data collected in the US and France from alcoholics with graded symptom severity b) Alcoholism-related white matter deficits measured on legacy and prospective DTI data collected in the US and France in alcoholics with graded symptom severity 2. Develop in the US and export to France fMRI and DTI protocols designed to examine and dissociate a) Cognitive frontocerebellar and frontal motor circuitry b) Limbic circuitry disruption to distinguish encoding from retrieval deficits in explicit memory.